Project 1 Summary Blocks to B cell memory: Dr. Charlotte Cunningham-Rundles: Common variable immune deficiency (CVID) is a primary antibody deficiency disease in which B cell development, including isotype switch, somatic hypermutation, differentiation into plasma cells and secretion of immunoglobulins is impaired. Due to prevalence, complications, and need for lifelong immunoglobulin therapy, CVID is one of the most clinically important primary immune defects. While the genetic causes of B cell dysfunction in CVID are unknown for most subjects, a growing number of autosomal recessive and more recently, dominant genes have been identified. About 8-10% of CVID subjects have mutations in the B cell receptor transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI). In addition to hypogammaglobulinemia, these subjects have striking lymphoid hyperplasia, splenomegaly and autoimmunity. TACI is highly expressed on marginal zone and CD27+ (memory) B cells, which secrete T cell independent (TI) Ab to carbohydrate antigens, essential in defense against bacterial disease. Unlike mice, human B cells have two TACI isoforms, a long and a short version; our data suggest that only the latter drives plasma cell differentiation, revealing additional complexity in this receptor system. Our group showed that TACI requires the cytoplasmic adaptor MyD88, and more recently that cytoplasmic TACI co-localizes with TLR9, MyD88, and the TNF receptor associated (TRAF) TRAF2 and TRAF6 in the endocytic compartment, suggesting intimate cytoplasmic cooperation between the TACI receptor and innate endosomal TLR pathways. Project 1 uses naturally occurring mutations in TACI, MyD88 and IRAK4, newly described defects in TRAF-interacting protein (TIFA) and members of the linear ubiquitination chain assembly complex, HOIL, HOIP, to explore how TACI isoforms are involved in the control of B cell growth, differentiation and the production of biologically important antibodies in humans. This project is closely linked to the study of tolerance in Project 2, marginal zone biology, bacterial defense, and the production of IgA in mucosal immunity in Project 3, and our progress in identifying new genetic defects leading to loss of B cell function and impaired antibody production to carbohydrate antigens, the topic of Project 4. These projects use naturally-occurring genetic immune defects to probe how normal human B cells are activated and controlled, knowledge essential for understanding how humans are efficiently immunized to produce protective antibodies and how the immune system achieves antibody memory while avoiding autoimmunity.